O40 – Acute kidney injury (AKI) causes persistent dysregulation of the leukocyte transcriptome
Author(s):
Background: Following severe blunt trauma, patients often develop organ injury. AKI is a known risk factor associated with worse outcomes following trauma. The Inflammation and Host Response to Injury (Glue Grant) showed that patients with a ‘complicated’ clinical course (>14 ICU days with organ injury) had a prolonged and exacerbated genomic response involving innate and adaptive immunity, and that the expression of 63 specific genes could predict a complicated outcome.
Hypothesis: We hypothesize that AKI will have a similar effect on these trauma patients’ genomic profile, looking at both genome-wide and the specific 63 genes.
Methods: 244 severely traumatized patients (ISS>15, no TBI, SBP hypotension or elevated BD, requirement for blood transfusion), genome-wide expressions were evaluated from blood neutrophils (PMN). The AKI cohort was based on RIFLE criteria (sCr increased x 2 or GFR decreased >50% plus UO <0.5ml/kg/h x 12h, n=59) within 3 days. These were compared to nonAKI patients (n=105). Samples were taken at 0.5, 1, 4, 7, 14, 21, and 28 days. Patients were cross-matched for gender, age, and ISS. Analysis consisted of identifying gene expression differences between AKI, nonAKI, and healthy subjects (p<.001). Individual gene changes (compared as gene expression fold change to control), functional pathway, and Gene Ontologies were analyzed. Distance from reference (DFR) was calculated for all gene sets as a ln measure of aberration in gene expression.
Results: At day 28, Gene Ontology showed that DFRs of pathways regarding inflammation/immunity were noted to be significantly greater (AKI vs nonAKI, respectively). These pathways include PMN and its surface molecules (4.3 vs 3.7), IL2 signaling (DFR 4.8 vs 4.3), and activation of the innate immune response (6.2 vs 5.8). Analysis of the 63 specific genes showed similar downregulation in immune response genes as seen in complicated patients, including: PDGF C, Prostaglandin-endoperoxide synthase 2, IFN-induced proteins, and Hect domain. Surprisingly, gene ontology analysis at 0.5 days also showed significantly different DFRs, indicating that genomic prediction of AKI early after trauma may be possible.
Conclusions: The presence of AKI in trauma patients appears to lead to both early and late PMN genetic differences. Alterations in these genetic responses may prove useful in screening for predisposition to AKI and its long term consequences, as well as possible therapies.